Chemical maps hint at drug's effects on schizophrenia

Antipsychotic drugs do most of their work in the brain, but they also leave behind in the bloodstream a trail of hundreds of chemicals that may be used in the future to direct better treatment for schizophrenia and other psychiatric conditions, say Duke University Medical Center researchers.

The study is among the first to use metabolomics -- the measurement of thousands of chemical byproducts of the body's cellular processes -- to look at a psychiatric disease and its response to therapy, according to the researchers.

"Doctors draw blood every day to look at metabolites such glucose and cholesterol and determine whether someone is at risk of diabetes or heart disease," said lead study investigator Rima Kaddurah-Daouk, Ph.D., an associate professor of biological psychiatry. "With metabolomics, we can look at thousands of metabolites to attain a more finely tuned map of an individual's overall health and gain information about how an individual is responding to a particular therapy."

In a report presented Friday, May 18, at the Society of Biological Psychiatry annual meeting, in San Diego, Kaddurah-Daouk said that chemical signatures measured by metabolomics were different for schizophrenia patients than for people without the disease. In patients treated with three different antipsychotic medications, the signatures differed according to which drug was used, giving researchers a tool to explore the metabolic side effects of these and other drugs.

The team's findings also appear in the May 2007 issue of the journal Molecular Psychiatry. The work was funded by the Stanley Medical Research Institute and NARSAD, both national mental health research associations.

Kaddurah-Daouk thinks this technology could lead to earlier diagnosis of schizophrenia. It may also begin to explain what makes some people more susceptible to schizophrenia, and why some people respond better to treatment than others or develop metabolic side effects, she added.

Schizophrenia is a devastating mental illness that is characterized by hallucinations, delusions and changes in outlook and personality. Currently there are no biological markers that can be used to establish a diagnosis or reliably predict response to treatment or how the disease will progress.

Although the prevailing theory has been that schizophrenia is caused by an imbalance in neurotransmitter molecules that help send messages between nerve cells in the brain, scientists recently have begun to investigate whether lipids, small fatty molecules such as cholesterol and triglycerides, also may play a role in the disease and in response to therapy.

The researchers, in collaboration with Lipomics Technologies, measured 300 different lipids in blood drawn from 50 patients with schizophrenia before and after treatment with the atypical antipsychotic drugs olanzapine, risperidone or aripiprazole. Lipomics specializes in diagnostic discovery with an emphasis on lipid metabolism. Atypical antipsychotics, a newer group of prescription medications used to treat psychiatric conditions, have fewer side effects than the older antipsychotics, but several still induce weight gain and diabetes.

Schizophrenic patients were found to have lower levels of the lipids used to make membranes involved in storing and communicating information in the brain. These lipid changes were partially reversed in patients treated with antipsychotic medications, said Joseph McEvoy, M.D., associate professor of biological psychiatry and study co-investigator.

"This technique allows us to identify the specific metabolic changes that are caused by the most commonly used drugs for schizophrenia," McEvoy said.

"This study is extremely important because it is giving us more information about how these drugs work," added Ranga Krishnan, M.D., chairman of psychiatry and senior study investigator. "Now we can begin to develop better medicines that target the specific metabolites important for the disease but not those that could lead to detrimental side effects."

Although some lipids are known to have detrimental effects on human health -- such as high levels of cholesterol that lead to heart disease -- many lipids have positive effects on basic human functions, including communication among all the cells of the body. Scientists are still trying to sort out which of the lipids that are modified in schizophrenia are beneficial and which ones result in metabolic side effects.

"Clearly we need to put forth a major effort to link the changes in the blood to what happens in the brain," Kaddurah-Daouk said. "If we can apply these findings to the mysteries occurring in the brain, then perhaps we can finally unlock the secrets of these devastating diseases."

Kaddurah-Daouk believes that this and other studies that explore metabolism at the global level have the potential to greatly impact medical practice. Future experiments focused on correlating these lipid signatures with the clinical outcomes of patients could yield an important tool for designing the best treatment for each patient, Kaddurah-Daouk said.

http://medschool.duke.edu/